Improving the treatment and prevention of drug addiction is an important goal for modern medicine, and ion channels have become attractive targets in the search for novel pharmacotherapies of drug addiction. Extracellular proton concentrations in the brain may be an important signal for neuronal function. Proton concentrations change both acutely, when synaptic vesicles release their acidic contents into the synaptic cleft, and chronically during ischemia, seizures, and other progressive neurological disorders. Acid-sensing ion channels (ASICs) are proton-gated cationic channels that are activated by a drop in extracellular pH. They are enriched in the mammalian brain with a high synaptic density. Accumulating evidence suggests that ASIC1a contributes to synaptic activity related to learning/memory and fear conditioning, and also plays a critical role in neurodegenerative diseases. Recently, we reported that functional ASIC1a is enriched in striatal medium spiny neurons as a dominant ASIC subtype. This subtype is sensitive to the psychostimulant cocaine, and its expression and function (ASIC currents) are upregulated in response to chronic cocaine administration. Further, the ASIC antagonist amiloride decreased sensitized motor responses to repeated cocaine and also decreased cocaine self-administration. Our pilot studies also reveal that ASIC1a, but not ASIC2, null mice showed a lack of behavioral sensitization to repeated cocaine. These findings raise an important question as to whether chronic cocaine treatment could progressively upregulate ASIC1a, leading to behavioral sensitization. In this application, we propose a series of coherent experiments to evaluate the role of ASIC1a, for the first time, in regulating behavioral sensitivity to repeated cocaine administration. Our hypothesis is that upregulation of ASIC1a activity contributes to behavioral sensitization to cocaine. The following two Specific Aims are proposed: (1), Define neurochemical and biophysical adaptations of ASICs to chronic cocaine administration; (2), Explore the functional role of ASIC1a in behavioral sensitivity to repeated cocaine. Data from this project will provide evidence and insights for a new molecular mechanism underlying drug addiction, and will ultimately contribute to the development of novel pharmacotherapies, by targeting ASIC1a, for the treatment of various mental illnesses stemming from substance abuse. We will use a multidisciplinary approach to test our hypothesis.